Parkinson's disease is a progressive neurodegenerative disease which usually affects elderly patients. The number of parkinsonian patients is growing with progressive aging of society. Parkinson's disease is characterized by impairment in coordinated motor function such as rest tremor, rigidity, akinesia, postural instability and the like. It is thought that Parkinson's disease results from deficiency of dopamine in the striatum, which is caused by degeneration of dopamine neuron in the substantia nigra. For that reasons, L-dopa or dopamine receptor stimulants are used for the treatment of Parkinson's disease.
L-dopa is a precursor of dopamine, and is metabolized to dopamine which exerts its efficacy in the brain. Since L-dopa has a very short serum half-life, L-dopa is administered usually in combination with a peripheral aromatic L-amino acid decarboxylase inhibitor and/or a catechol-O-methyltrasferase inhibitor, which inhibit the metabolism of L-dopa in the body. Catechol-O-methyltrasferase (thereinafter referred to as “COMT”) is an enzyme that catalyze the transfer of the methyl group of S-adenosyl-L-methionine to chatechol substrates. The inhibition of the COMT enzyme slows down the metabolism of L-dopa to 3-O-methyl-L-dopa, which results in the significant increase in serum half-life of L-dopa and the amount of L-dopa crossing the blood-brain-barrier. In this way, a COMT inhibitor, when administered in combination with L-dopa, increases the bioavailability of L-dopa and prolongs its effects (see Non Patent Literature 1).
COMT inhibitors are also expected to be useful for treating or preventing hypertension since COMT inhibitors exhibit urinary sodium excretion promoting activities (see Non Patent Literature 2). COMT inhibitors are also expected to be useful for treating or preventing depression (see Non Patent Literature 3).
A variety of COMT inhibitors have been reported recently. Among them, tolcopone (3,4-dihydroxy-4′-methyl-5-nitro-benzophenone, Patent Literature 1) and entacapone ((E)-2-cyano-N,N-diethyl-3-(3,4-dihydroxy-5-nitrophenyl) acrylamide, Patent Literature 2) are the most potent COMT inhibitors known to date. Tolcapone or entacapone are clinically administered to patients for treating Parkinson's disease. However, it has been reported that tolcapone causes severe liver function damage, and can only be used in parkinsonian patients strictly with regular monitoring of liver function (see Non Patent Literature 4). On the other hand, entacapone has less potent efficacy than tolcapone, and has a problem to have a very limited duration of effect (see Non Patent Literature 5). Accordingly, there is still a need for novel COMT inhibitors with potent COMT inhibitory activities and a desirable safety profile.
Patent Literature 3 discloses substituted nitrocatechol derivatives such as carbonic acid 4,5-dibenzoyl-2-ethoxy-carbonyloxy-3-nitrophenyl ester ethyl ester; (6-benzoyl-3,4-dihydroxy-2-nitrophenyl)phenylmethanone; 3,4-dihydroxy-2-nitrophenyl)phenylmethanone and the like, which have COMT inhibitory activities (see examples 4 and 61 in Patent Literature 3). However, the results of table 2 in Patent Literature 3 show that the liver COMT inhibitory activities of these compounds are less potent as compared with that of entacapone.